The objective of this project is to develop new progesterone formulation(s) that are effective as hormone replacement therapy-- protecting the coronary arteries against hyperreactivity. Such hyper- reactivity results from the deficiency of progesterone after the cessation of ovarian function. The anticipated new product, to be proved feasible here, developed in phase 2, and marketed in phase 3, will be a formulation that will be accepted by post-menopausal women sufficiently well to allow compliance of the majority of those who initiate hormone replacement therapy--for durations of 50 years or even more. Protection provided by progesterone for the cardiovascular system can be expected to be lost in a matter of 2 weeks after progesterone declines; therefore progesterone should be provided in a form with which compliance can be expected. The skin cream formulation is well accepted by women, and has optimal pharmacokinetics for a once a day treatment that will reduce the risk of cardiovascular events including ischemic heart disease and coronary vasospasm. Even though the risk of death due to cardiovascular causes is nearly 50% for post-menopausal women, and is far greater than any other risk, the presently available forms of hormone replacement therapy are neither well understood nor readily accepted. PROPOSED COMMERCIAL APPLICATION: The commercial application will be a percutaneous formulation of progesterone with absorption enhancers comprising a method to produce a blood level that minimizes the risk of cardiovascular disease. The product is anticipated to find widespread application in hormone replacement therapy, resulting in improved patient acceptance, and thus a large growing market.